Acne is a disease of the skin in which the pilosebaceous structures of the skin become inflamed, leading to the formation of comedones, pustules, and nodules. It is generally believed that acne arises when hyperkeratosis of the pilosebaceous structure wholly or partially blocks the opening of the structures, resulting in comedones filled with sebum, keratin, and Propionibacterium acnes (“P. acnes”). These lesions are commonly identified as acne. P. acnes naturally occur in normal skin but is especially and characteristically present in acne lesions. Acne naturally varies in severity from mild to very severe. People with severe (deep, or cystic) acne, on the other side, have numerous large, red, painful pus-filled lumps (nodules) that sometimes even join together under the skin into giant, oozing abscesses. Depending on the degree of severity and pronounced appearance, acne can be acne vulgaris, acne comedonica, acne papulo pustulosa, acne conglobata, etc. which are, inflammatory acne or non-inflammatory acne.
Conventional acne treatments have a varied range of alternatives available which includes, topical therapy using benzoyl peroxide, keratolytic agents like salicylic acid; local or systemic treatments using antibiotics like tetracycline, minocycline, doxycycline, clindamycin, erythromycin, azithromycin, macrolides, co-trimoxazole, and trimethoprim or using retinoids like tretinoin, adapalene, tazarotene, isotretinoin, metretinide, retinaldehyde, and β-retinoyl glucuronide; hormonal therapy—to prevent the effects of androgens on the sebaceous gland using norgestimate with ethinyl estradiol, and norethindrone acetate with ethinyl estradiol; various physical treatments and the like or combinations thereof. Suitable treatment option can be decided considering severity of acne and therapeutic effect of available drug, for example, oral antibiotics are indicated mainly in moderate-to-severe inflammatory acne whereas oral retinoids are preferred in case of severe, scarring and/or refractory acne.
While a variety of acne treatments do exist, retinoids have been widely described for treatment of a number of dermatological disorders, including both acne and seborrhoea. The available topical dosage forms have been reported to produce skin irritation (dermatitis) that may include erythema, scaling, peeling, drying, pruritus, and sensations similar to sunburn. Oral retinoids are indicated in severe, moderate-to-severe acne or lesser degree of acne producing physical or psychological scarring, unresponsive to adequate conventional therapy. Orally administered retinoic acid—13-cis retinoic acid (isotretinoin) revolutionized the treatment of severe forms of acne when it was introduced in 1982, and continues to be a widely used single therapy for treating severe acne. Oral isotretinoin is so effective against acne because it is the only treatment affecting all major etiological factors, including, in particular, a substantial reduction of sebum production by inhibition of the lipogenesis, as well as a reduction of the size of sebaceous glands of the patient. Thus, it is established as the gold standard of acne therapy, capable of long-term remission in about 80% of patients with severe acne.
At present, oral retinoic acid is available as various capsules with options to choose from with food or without food. Retinoic acid like isotretinoin is a synthetic retinoic acid derivative, also known as 13-cis retinoic acid, which is chemically (2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoic acid. It has very low water solubility and thus has formulating challenges to provide oral dosage forms. There are few arts which describes oral formulations of isotretinoin. For example, WO 2000/025772, WO 2015/181802, WO 2015/186039 A1, WO 2016/016742 A1, WO 2016/051288 A1, WO 2016/189481 A1, WO 2016/193779 A1, U.S. Pat. Nos. 6,740,337, 7,435,427 and 8,367,102 relate to micronized isotretinoin present as dispersion, suspension or semi-solid suspension formulated for oral administration, which may also include oily vehicle; IN 249181 discloses isotretinoin tablets prepared with fumaric acid.
Commercially available oral isotretinoin formulations comprise an oil/lipid based vehicle. Retinoids have side effects of developing high levels of cholesterol and other fats in the blood among other known teratogenic effects. The use of oil/lipid based formulations may further increases chances of such adverse events. As such, there remains an unmet need in the art for oral formulations of retinoic acid, free of such oily/lipidic vehicles, which can also provide efficient dosing without regard to food effect/reduced food effect. Additionally, considering teratogenic nature of retinoic acids, there is also a continuing need to provide once-daily doses, as opposed to the currently prescribed divided daily doses.